Substituted indenoimidazoles

ABSTRACT

NEW INDENOIMIDAZOLES USEFUL IN THE INHIBITION OF PHENYLETHANOLAMINE-N-METHYL TRANSFERASE.

United States Patent 3,792,057 SUBSTITUTED INDENOIIVHDAZOLES Norman P.Jensen, Watchung, and Tsung-Ying Shen and Thomas B. Windholz, Westfield,N.J., assignors to Merck & Co., Inc., Rahway, NJ.

No Drawing. Filed May 14, 1971, Ser. No. 143,665 Int. Cl. C07d 49/36 US.Cl. 260-309 3 Claims ABSTRACT OF THE DISCLOSURE New indenoimidazolesuseful in the inhibition of phenylethanolarnine-N-methyl transferase.

This invention relates to new chemical compounds. More specifically,this invention relates to new indenoimidazoles. Still more specifically,this invention relates to compounds having the following generalformula:

OJlwherein R is hydrogen, methylthio or and R R R and R each may behydrogen, trifiuoromethyl, halo or nitro.

A final step in epinephrine biosynthesis is the transfer of a methylgroup from S-adenosylmethionine to the amine nitrogen of norepinephrine.This step is catalyzed by phenylethanolamine-N-methyl transferase. Thisinvention further relates to a method of inhibiting the formation ofphenylethanolamine-N-methyl transferase utilizing the compounds of thisinvention, thereby resulting in a decrease in the formation of adrenalepinephrine.

These compounds have clinical utility in situations Where there is aselective overproduction of adrenal epinephrine such as in the treatmentof narcotic addiction, for example the management andcontrol of morphinewithdrawal, the treatment of various emotional states, for exampleanticipatory, painful and anxiety states in normal and psychiatricsubjects, in particular for the treatment of anxiety neurosis, and theprophylactic control of cardiovascular disorders characterized byincreased heart rate and cardiac output, management of heart failure,cardiac shock or other situations in which stress exerts pressure uponcardiac performance, as, for example, the management of myocardialinfarctions.

The compounds of this invention also are useful as fungicides andcoccidiostats and may be used to treat diseases and conditionscharacterized by the presence of coccidia or fungi.

The compounds of this invention wherein R is a phenyl group are preparedby reacting the appropriate indanone with a benzamidine derivative inthe presence of ammonia. When R is hydrogen or methylthio, theappropriate indanone is converted to its 2-amino derivative which isreacted with potassium thiocyanate to form the correspondingindenoimidazole.

A preferred embodiment of this invention is a method of inhibitingphenylethanolamine-N-methyl transferase which comprises theadministration to a patient (animal or human) of a therapeuticallyeffective amount of the compounds of the above formula. In general thedaily dose can be from 0.05 mg./kg. to 150 mg./kg. per day andpreferably from 1 mg./kg. to 100 mg./kg. per day, bearing in mind, ofcourse, that in selecting the appropriate dosage in any specific case,consideration must be given to the patients weight, general health,metabolism, age and other factors which influence response to the drug.

Another embodiment of this invention is the provision of pharmaceuticalcompositions in dosage unit form which comprise from about 1 mg. to 500mg. of a compound of the above formula.

The pharmaceutical compositions may be in a form suitable for oral use,for example, as tablets, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixers. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to provide apharmaceutically elegant and palatable preparation. Tablets contain theactive benzimidazole ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable formanufacture of tablets. These excipients may be, for example, inertdiluents, for example calcium carbonate, sodium carbonate, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example maize starch, or alginic acid; binding agents, suchas starch, gelatin, or acacia, and lubricating agents, for examplemagnesium stearate, stearic acid or tale. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with an oilmedium, for example arachis oil, liquid parafiin or olive oil.

Aqueous suspensions contain the active benzimidazole in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxy-cetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol, for example polyoxyethylene sorbitol mono-oleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example, ethyl, or n-propyl, p-hydroxy benzoate, oneor more coloring agents, one or more flavoring agents and one or moresweetening agents, such as sucrose, saccharin, or sodium or calciumcyclamate.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparafiin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soya bean lecithin, andesters of partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan-mono-oleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectablepreparation, for example as a sterile injectable aqueous suspension in anon-toxic parenterally-acceptable diluent or solvent, for example as asolution in 1:3-butane diol.

The pharmaceutical compositions may be tableted or otherwise formulatedso that for every 100 parts by weight of the composition there arepresent between 5 and 95 parts by weight of the active ingredient. Thedosage unit form will generally contain between about 100 mg. and about500 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion it is apparent that thecompositions of this invention can be administered orally orparenterally. The term parenteral as used herein includes subcutaneousinjection, intravenous, intramuscular, or intrasternal injection orinfusion techniques.

The following examples are presented to further illustrate theinvention.

EXAMPLE 1 (A) 4-trifiuoromethylbenzimidic acid ethyl ester hydrochlorideA mixture of 17.1 g. of p-trifiuoromethylbenzonitrile and 25 ml. ofabsolute ethyl alcohol is stirred and cooled with an ice bath before 75ml. of ethyl alcohol which was cooled to C. and saturated with hydrogenchloride is added. After four days at C., the solution is concentratedin vacuo to a slush, and ethyl ester is added to precipitate4-trifluoromethylbenzimidic acid ethyl ester hydrochloride, M.P. 185-186C.

(B) 4-trifluoromethylbenzamidine hydrochloride A 7.5 g. portion of4-trifluoromethylbenzimidic acid ethyl ester hydrochloride is dissolvedin 40 ml. of absolute ethyl alcohol, and a 5% solution of ammonia-ethylalcohol is added in 1 ml. portions with stirring until the odor ofammonia persists. After standing two days, the solution is concentratedto a solid which is washed well with ethyl ester to give4-trifluoromethylbenzamidine hydrochloride, which is used withoutfurther purification.

(C) 2-(4-trifluoromethylphenyl)-1,4(8)-dihydroindeno- [1,2d] -imidazoleA mixture of 3.24 g. of 2-bromo-1-indanone in 30 ml. of chloroform and3.30 g. of 4-trifluoromethylbenzamidine hydrochloride in ml. of water isstirred vigorously, and 1.8 g. of potassium hydroxide in 10 ml. of wateris added. The mixture is stirred and refluxed for 3 hours before theresultant precipitate is collected and washed with water and chloroformto give 0.80 g. of intermediate hydroxy compound. A 0.70 g. portion ofthis intermediate is refluxed 10 minutes in 7 ml. of acetic acid. Theacetic acid is removed in vacuo and the residue extracted with 10 ml. ofethyl ester. The ethyl ester extract is concentrated to crude product,which is recrystallized four times from methyl alcohol to give product,M.P. 206211 C.

Using the same reaction conditions and techniques, 4-chloromethylbenzylamidine and 4 nitromethylbenzamidine are reacted with2-bromo-1-indanone to produce 2- (4-chloromethylphenyl)-l,4(8)dihydroindeno [1,2d]- imidazole and 2-(4-nitromethylphenyl)-1,4(8)dihydroindeno-[ 1,2d] -imidazole.

EXAMPLE 2 Indeno- 1 ,2d] -imid azole A 1.0 g. portion of2-mercaptoindeno-[1,2d]-imidazole and 7-8 g. of Raney nickel are stirredand refluxed in 30 ml. of ethyl alcohol for one hour. While still hotthe mixture is filtered to remove the 'Raney nickel, which is washedwith 3 x 10 ml. of ethyl alcohol. The filtrate and washings areconcentrated to yield a pale green cure product, which is purified bysublimation, M.P. 168- 172 C.

EXAMPLE 3 2-methylthioindeno-[ 1,2d] -imidazole To a slurry of 1.88 g.of 2-mercaptoindeno-[1,2d]- imidazole in 50 ml. of tetrahydrofuran isadded 0.70 ml. of iodomethane. After 16 hours of stirring, theprecipitate is collected and stirred with excess 1 N sodium hydroxide.Collection of the precipitate yields product, M.P. 166- 168 C.

EXAMPLE 4 (A) 6-chloro-1-indanone -A mixture of 35 g. ofp-chlorohydrocinnamic acid and 414 g. of polyphosphoric acid is heatedon a steam bath for one-half hour. Dilution with 3 liters of water givesa precipitate which is dissolved in ethyl ester. The ethyl estersolution is washed with sodium bicarbonate, steam distilled, and thesteam distilled material recrystallized from ethyl alcohol to giveproduct, M.P. 70-73 C.

(B) 6-chloro-2-isonitroso-l-indanone A solution of 5.7 g. of6-chloro-l-indanone in 60 ml. of benzene is stirred, and hydrogenchloride gas is bubbled in as 4.8 g. of t-amylnitrite is added dropwiseover a period of 15 minutes. Addition of hydrogen chloride is continued20 minutes longer. The mixture is stirred 15 hours before product iscollected, M.P. ZOO-204 dec.

Using the same reaction conditions and techniques, 5- bromo-l-indanone,6 bromo 1 indanone, 5-chloro-1- indanone, 5fluoro-1-indanone,6-fluoro-1-indanone and 5-nitro1-indanone are reacted with t-amylnitriteto produce 5-bromo-2-isonitroso-l-indanone, 6-bromo 2isonitroso-l-indanone, 5-chloro-2-isonitroso-1 indanone, 5-fluoro-2-isonitroso-l-indanone, 6-fluoro-2 isonitroso 1- indanone and5-nitro-2-isonitroso-l-indanone, respectively.

(C) 2-amino-5-chloro-l-indanone To a stirred mixture of 9.13 g. ofstannous chloride dihydrate in 13 ml. of concentrated hydrogen chlorideis added portionwise 3.6 g. of 6-chloro-2-isonitroso 1 indanone over aperiod of one and one-half hours. The temperature is maintained at lessthan 40 C. with intermittent cooling. After stirring for one-half hourat room temperature and one-half hour at C., the mixture is cooled and500 ml. of water is added. The mixture is stirred and hydrogen sulfideis bubbled in until no further precipitate is obtained. Solids areremoved by filtration, and concentration of the filtrate gives crudeproduct, which is purified and recrystallized from methyl alcoholethylester to yield product, M.P. 200 dec.

(D) (7)-chloro-2-mercapto-1,4(8)-dihydroindeno- 1,2d] -imidazole Amixture of 1.44 g. of 2-amino-5-chloro-l-indanone and 0.675 g. ofpotassium thiocyanate are refluxed for 15 minutes in 45 ml. of glacialacetic acid. After cooling, crude product is collected on a filter andis used without further purification.

(E) 5' (7 )-ch1oro-1 ,4 8 -dihydroindeno-[ 1,2d] -imidazole A 310 mg.portion of crude 5(7)-chloro-2-mercapto- 1,4(8)-dihydroindeno- [1,2d]-imidazole is treated with Raney nickel according to the procedure ofExample 2 to give crude product which is purified by preparative TLCmethyl alcohol-chloroform on silica gel G) followed by trituration withether to yield product, M.P. 19820l.5 C.

The indanones produced by the procedure of Example 4(B) are reacted bythe procedures of Examples 4(C),

4(D) and 4(E) to produce the corresponding imidazoles.

EXAMPLE 5 5 (7) -chloro-2-rnehylthio-1,4(8 )-dihydroindeno- 1,2d]-

imidazole A 0.31 g. portion of crude 5(7)-chloro-.2-mercapol,4(8)-dihydroindeno [1,2d] imidazole is treated with iodomethane asdescribed in Example 3 to yield product, M.P. 219223 C.

EXAMPLE 6 A mixture of 250 parts of 2-(4-trifiuoromethylphenyl)-1,4(8)-dihydroindeno-[1,2d]-imidazole and 25 parts of lactose isgranulated with suitable water, and to this is added 100 parts of maizestarch. The mass is passed through a l 6-mesh screen. The granules aredried at a temperature below 60 C. The dry granules are passed through a16-mesh screen, and mixed with 3.8 parts of magnesium stearate. They arethen compressed into tablets suitable for oral administration.

EXAMPLE 7 A mixture of 50 parts of indeno-[1,2d]-imidazole, 3 parts ofthe calcium salt of lignin sulfonic acid, and 237 parts of water isball-milled until the size of substantially all of the particles ofbenzyl ethyl sulfoxide is less than 10 microns. The suspension isdiluted with a solution containing 3 parts of sodiumcarboxymethylcellulose and 0.9 part of the butyl ester ofp-hydroxybenzoic acid in 300 parts of water. There is thus obtained anaqueous suspension suitable for oral administration for therapeuticpurposes.

EXAMPLE 8 A mixture of 250 parts of Z-amino-S-chloro-l-indanone, 200parts of maize starch and 30 parts of alginic acid is 6 mixed with asufiicient quantity of a 10% aqueous paste of maize starch, andgranulated. The granules are dried in a current of warm air and the drygranules are then passed through a 16-mesh screen, mixed with 6 parts ofmagnesium stearate and compressed into tablet form to obtain tabletssuitable for oral administration.

EXAMPLE 9 2. A compound of the formula rug wherein R is halo.

3. A compound of the formula wherein R is halo.

References Cited R. Paul et al.: J. Prakt. Chem., vol. 28, pp. 297-304(1965).

HARRY I. MOATZ, Primary Examiner UJS. Cl. X.R.

260564 R, 566 R, 570.5 C, 590, 647; 424-273

